Histone deacetylase inhibitors (HDACIs) are potent anticancer drugs, and
suberoylanilide hydroxamic acid is used for the treatment of
cutaneous T-cell lymphoma patients. We synthesized a novel hydroxamate-based HDACI,
CG0006, and assessed its antiproliferative effects on the NCI-60
cancer cell panel and cell lines from liver and
stomach cancers that are common in Korea. Micromolar levels of
CG0006 induced cell death in several breast, central nervous system, colon, hematopoietic, lung,
melanoma, ovarian, prostatic, renal, and
stomach cancer cell lines. We further analyzed cell death mechanisms activated by
CG0006 in HCT116 (
colon cancer) and K562 (
leukemia) cells. First, to test the activity of
CG0006, we analyzed acetylation of substrates of HDACs and effect on gene expression.
CG0006 increased acetylation of
histone 3,
histone 4, and
tubulin in a time-dependent and dose-dependent manner in both HCT116 and K562 cells. Moreover,
CG0006 increased the
mRNA level of p21 and decreased that of Bcl-xl efficiently in HCT116 cells. Cell cycle analysis showed G2-M arrest, and increased apoptosis in populations of HCT116 and K562 cells treated with
CG0006. Western blot analysis showed that
CG0006 increased levels of p21 in HCT116 cells and of p21 and p27 in K562 cells. In addition,
CG0006 activated
caspase-9,
caspase-3, and
caspase-8. These results indicate that
CG0006 induces death in HCT116 and K562 cells through both intrinsic and extrinsic apoptotic pathways. The HDACI
CG0006 may be a potent anticancer
drug for solid
tumors and
leukemia.